Bicycloazaoctane derivatives



BICYCLOAZAOCTANE DERIVATIVES Leonard M. Rice, Baltimore, Md., andCharles H. Grogan, Falls Church, Va., assignors to The Geschickter Fundfor Medical Research, Inc., Washington, D. C., a cor-- poration of NewYork N Drawing. Application January 4, 1955, Serial No. 479,872

9 Claims. (Cl. 260-239) This invention relates to compositions ofmatter, particularly to chemo-therapeutic organic compounds and methodsof their preparation, and more particularly to compounds of value in thetreatment of cardio-vascular and other diseases.

Specifically the invention relates to bicycloazaoctane and the simplesalts and the monoand bis-quaternary salts of bicycloazaoctane.

Accordingly, it is a basic object of the present invention to providenovel organic compounds and methods for the preparation thereof.

Another object is to provide novel, physiologically active compoundscharacterized by chemotherapeutic or medicinal properties, particularlyhypotensive activity.

A more specific object is to provide novel compounds, namely,bis-quaternary salts o'fbicycloazaoctane.

Another and equally important object of the invention is the provisionof methods of synthesizing the novel compounds referred to in theforegoing objects.

These and other objects and the manner in which they are accomplishedwill become apparent to those conversant with the art from the followingdescription of the general class of compounds and certain specificexamples of particular members thereof as well as general and specificmethods of their synthesis.

The novel chemotherapeutic compounds of the present invention arebis-quaternary salts of l-methyl-S-dimethyl- 3-azabicyclo (3,2,1) octane(camphidine) the base itself being shown in the formula following:

Generally stated, the novel compounds discovered are obtained by formingthe N-dialkylaminoalkyl 'imides of alkyl group with from 1 to 6 carbonatoms, an alkylene group containing 3 carbon atoms or, the structure mayrepresent a heterocyclic ring namely, morpholine, piperidine,pyrrolidine or piperazine.

The simple salts of the bases illustrated by Formula 1 are shown byFormula 2.

X- X- R and the monoand bis-quaternary salts of these bases by Formulae3(a) and 3(1)), respectively:

In Formulae 2, 3(a) and 3(5), A represents the parent bicycloaZo-octanenucleus and X" represents an anion namely, iodide, chloride, bromide,acetate or sulfate. R, R and n have the same meaning in all formulae asdescribed above for Formula 1. In the three latter formulae, i. e., 2,3(a) and 3(b), the site of both simple and quaternary salt formation onthe nucleus A is always the nitrogen at position 3. In the. quaternaryand bisquaternary salts, R" represents a simple alkyl group having oneto three carbon atoms. R may be the same as,

'or'ditferent from, R and/or R in any of the formulae given. V

Of the compounds described above, the free bases and simple saltspossess antihistaminic and bronchiodilatory activity. The quaternarysalts of these bases, and particularly the bis-quaternary salts thereof,possess a marked hypotensive activity in mammals at a low dosage leveland at the same time a favorable therapeutic ratio. In addition, thefree bases, Formula I, possess in varying degree a very discrete moldyor earthy odor which is of value in obtaining this rare type of odor inperfumery or other special preparations in which these particularodoriferous qualities are desired.

The following examples of specific compounds and methods will illustratethe manner in the general synthesizing procedure which may be applied toobtain particular members of the class of compounds discovered. It willbe understood, however, that the following examples are not nor are theyintended to be exhaustive of all compounds embraced by the presentinvention.

EXAMPLE I N-dimethylaminoethyl-D-camphidine, simple salts and quaternarysalts The free base. -The free base has prepared as follows: grams ofN-dimethylaminoethyl-D-camphorimide dissolved in 300 ml. of anhydrousethyl ether was added dropwise to a rapidly stirred solution of 16 grams(0.44 mole) of lithium aluminum hydride (LAH) dissolved in 600 ml. ofanhydrous ethyl ether. The addition was at such a rate as to justmaintain a gentle reflux of the ether. After the addition was complete,the mixture was stirred under reflux for an additional 2 hours andallowed to stand over night. The reaction mixture was then decomposed bythe dropwise addition of water at such a rate as to just cause reflux ofthe ether. When the evolution of hydrogen ceased, a slight excess ofwater was added and the mixture stirred for several hours. The inorganicmaterial was filtered oil? and the residue washed several -times withether. The ethereal filtrate was dried over anhydrous sodium'sulphate,the ether was stripped E and the residue was vacuum distilled to yield33 grams of N- dimethylaminoethyl-D-camphidine base having a boilingpoint of 64 C. at 0.4 mm.; N =1.478.

The dihydrochloride.The dihydrochloride, a crystalline hygroscopic salt,was prepared by treating the free base dissolved in ethanol with asaturated ethanolic-I-ICl solution. It had a melting point 2634 C. Onrecrystallization from absolute methanol-anhydrous other it had amelting point of 265-266 C. and an experimentally determined chlorideion content of 23.41% as compared to 23.85% theoretically calculated.

The m0n0methi0dide.-The monomethiodide was readily obtained incrystalline form by treatment of the free base dissolved in absoluteisopropanol with an excess of methyl iodide in a closed system. It had amelting point of 239240 C. Recrystallization of the salt from anhydrousmethanol-anhydrous ether gave the compound with a melting point'of 241C. The iodide ion calculated theoretically was 34.65% and that found tobe present in this compound was 34.46%.

The dimethiodide.The dimethiodide could not be obtained by simplereaction of thefree base with methyl iodide in large excess in methanolor ethanol. only the monomethiodide obtained was prepared by adding thefree base to pure methyl iodide. For this reason and on the basis of thefollowing experiments, it is concluded that the monomethiodide describedabove must be the quaternary salt of the side chain nitrogen and notthat of the ring nitrogen. Examination of a molecular model of thismolecule showed that the ring nitrogen ofiered considerable hindrance tothe formation of a quaternary salt here. The following experimentsillustratethe difliculty of quaternizing the ring nitrogen and themanner in which this was finally accomplished.

Experiment 1.4 grams of the free base plus 10 ml. of methyl iodide wererefluxed for 2 hours in 50 ml. of

In fact,

anhydrous methanol and yielded a white crystalline solidhaving a meltingpoint of 232-234 C. On analysis, the

percentage of iodide ion introduced was found to be 36.76% or onlyslightly higher than the 34.65% theoretically required for themonomethiodide.

Experiment 2.Repeating Experiment 1 and refluxing for 12 hours inisopropanol gave a crystalline product i with 38.95% iodide ion.

Experiment 3.Repeating Experiment 1 and refluxing .the free base in puremethyl iodide for 3 days gave a discolored crystalline material with 44%iodide ion. The

' theoretical iodide ion content for the dimethiodide is indicatingtherefore that the compound obtained by means of Experiment 4 is in thedimethiodide.

EXAMPLE II N-dimethylaminopropyl-DL-camphidine, simple salts andquaternary salts Free base.-The free base was prepared as describedunder Example I by reducting 40 grams of the corresponding imide with 16grams of LAH in anhydrous ether medium. The free base was obtained in 31grams yield and had a boiling point of 7072 C. at 0.1 mm.; n =1.4770.

The dihydrochloride.The dihydrochloride was prepared as described underExample I and had a melting point of 290292 C. Chloride ion calculatedtheoretically, 22.78%; chloride ion found by analysis, 22.92%.

The m0n0methi0dide.-The monomethiodide, melting point 237-238 C., wasprepared by reaction of the free base with an excess of methyl iodide inanhydrous methanol. Its theoretical iodide content is 33.37% and inanalysis of the compound so obtained was 33.55%.

The dimethiodide.-The dimethiodide was prepared above under Experiment4, Example I, the heating at 250 F. being carried on for 8 hours. It hada melting point of 269271 C. and an iodide content of 48.63% as comparedwith a theoretical iodide content of 48.60%.

EXAMPLE IH N-diethylaminoethyl-D-camphidine, simple salts and quaternarysalts The free base-The free base was prepared as described underExample I, above. Reduction of 40 grams of the imide yielded 29 grams ofthe base, which has a boiling point of 7074 C. at 0.1 mm.; n =1.4780.

The dihydr0chl0ride.The dihydrochloride ofN-diethylaminoethyl-D-norcamphidine was also prepared as in Example Iand was found to have a melting point of 254.5-255.5 C. and a chlorideion content of 21.77%

the manner described under Experiment 4, Example I,

above. 'It has a melting point of 235-236 C. An analysis showed aniodide content of 47.13% as compared to a 47.16% theoretical value.

EXAMPLE IV N-diethylaminopropyl-D-camphidine, simple salts andquaternary salts The free base-This base was prepared as described underExample I; 40 grams of imide yielded 32 grams of the base which had aboiling point of 8387 C. at 0.06 mm.; n =1.4778.

The dihydrochl0rz'de.This salt was prepared as described under Example Iand has a melting point of 212- 214 C. The analysis of the salt forchloride ion resulted in a finding of 20.74% as compared with atheoretical content of 20.89%

The m0n0methiodide.-The salt was prepared as described under Example I.Its melting point is 196-198 C. and it has an iodide content of 31.13%as compared -with a theoretical value of 31.07%

The dimethiodide-This compound was prepared as described underExperiment 4, Example I. Its melting point is 217219 C. and its iodidecontent is 45.88%

compared with 46.12% theoretically calculated.

Other N-dialkylaminoalkyl substitutions have been prepared in similarfashion as shown by the following tables:

-,Table I shows the bases and Table II shows the various salts,

TABLE I Bases N-DIALKYLAMINOALKYL-l-METHYL-8,8-DIMETHYL-3-AZABICYCLO[3.2.1] OCTANES Analysis. Percent B. P., N-substltutlon Formula 0. mm.Carbon Hydrogen Nitrogen on Calcd Found Calcd. Found Caled. Foundl-dimothylamiuoethyl CuHggNg 6-1- 66 0.4 74. 94 75.05 12.58 12.44 12.4912. 79 1. 4781 2-diethylaminoethyl... CrsHsiNr 70- 74 O. 1 76.12 76. 2812. 78 12.86 11.10 11.28 1. 4780 i e wam opmpr CrsHsoN-r 76- so 0.275.56 75. 21 12.68 12. 40 11.75 11.67 1.4772

4-dunethy1amin0pr0p3 OisHzoNz 70- 0. 1 75. 56 75. 30 12. 68 12.30 11. 7511. 54 1. 4770 y opropyl. C11Ha4Nz 81- 89 '0. 05 76. 62 76.63 12.8612.73 10.51 10.44 1.4778

fi-diethylarninobutyl CrsHaaNz 96-100 0. 1 77. 07 77. 06 12. 94 12. 929. 99 9. 67 1. 4771 7-diethylaminoamyl. CmHagNz 100-105 0. 1 77.48 77.63 13. 01 13. 10 9. 51 9. 36 1.4766

8-dlbutylarninopropyl. CzrHqtNz 106-110 0. 1 78. 19 77. 94 l3. l2 12. 958. 69 8. 23 1. 4756 9-morpholinoethyl CwHsoNzO 102-105 0. 1 72. 13 71.85 11. 35 11. 36 10. 52 10. 31 1. 4954 10-pyrrolidinoethyl CmHguNg 88-93 0.2 76. 74 76. 49 12.08 12.42 11.19 10.79 1. 4960 TABLE IIDerivatives of compounds in Table I H01 Ionic Chlorine MonomethiodideDimethlodide lonic Iodine Ionic Iodine Formula M. R, C. Oalcd. FoundFormula M. P., 0. Formula Calcd. Found Calcd. Found 1. OuHsnClzNa263-264 23. 85 23. 41 C E 3 11921.. CmHarIaNz 244-245 49. 94 50. O5 2.CrsHarCltNi. 254. 5-255. 5 21. 66 21. 77 47. 16 47. 63 3. CH32C12N2.290-291 22. 78 22.74 48.60 48. 32 4. laHazGlzNz. 290-291 22. 78 22.9248. 60 48. 63 5. CuHasClzNz. 212-214 20. 89 20. 74 46.12 45. 88lBHBzG12'N2. 286-286 20.07 19.97 44.98 44.46 7. CmHroClzNz. 274-275 19.29 19.59 43. 89 44. 15 8. CzrHnClzNz. 138-140 17.93 17.94 41.86 41.57 9.CmHazCle 1 263-264 20. 90 20.72 46.13 45. 96 10. CmHmChNz. 263-265 21.9322.10 O17H33LN2. CmHauIgN: 250-251 47. 51 47.85

As previously mentioned, the novel compounds disclosed herein are highlyefficacious in the treatment of physiological disorders requiringanti-histaminic, bronchiodilatory, and hypotensive etfects. For reliefof hypertension milligrams of the quaternary salts in parenteralsolution may be administered once a day or -250 milligrams may be givenorally in the form of tablets, capsules or the like.

As a respiratory stimulant, the base compounds may be given orally or byinjection in 50 milligram doses.

From the foregoing description of a novel class of compounds, particularexemplary members of the class and methods of synthesizing same, it willbe understood that, on the basis of the discovery and knowledgedisclosed herein, other specific compounds can be made and variations inthe methods of synthesis resorted to. Therefore, the specific compoundsand methods disclosed herein are to be considered in all respects asillustrative and not restrictive, the scope of the discovery beingindicated by the appended claims rather than the foregoing description,and all specific compounds and variations and methods which come withinthe meaning and range of equivalency of the claims are thereforeintended to be embraced there- This application is acontinuation-in-part of our application Serial No. 388,062, filedOctober 23, 1953, entitled Bicycloazaoctane Derivatives, now abandoned.

We claim:

1. A compound selected from the group consisting of (1) compounds havingthe formula where, in said formula, n is a number from 1 to 5 and R is amember of the group consisting of dialkyl groups each alkyl group having1 to 6 carbon atoms and radicals forming, together with the nitrogenatom to which they are attached, heterocyclic groups consisting ofmorpholine,

' piperidine, piperazine and pyrrolidine, and (2) the acid ReferencesCited in the file of this patent FOREIGN PATENTS Germany Nov. 12, 1921OTHER REFERENCES Auwers: Chem. Abst., vol. 17, p. 1644 (1923).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS HAVINGTHE FORMULA